79-P: FURTHER EXPLORATION OF HLA REGION ASSOCIATIONS WITH LUNG CANCER RISK

Abstract

Genome-wide association studies (GWAS) have identified multiple lung cancer associations within HLA region, BAG6 rs3117582 being the strongest. Other cancer associations nearby have also been reported (CCHCR1 rs130067 and MDC1 rs28986317/prostate cancer; MICB rs3130922/glioma; HSPA1B rs2763979/poor survival in lung cancer). BAG6 is heat shock-induced, and rs3117582 association may be due to its modification of stress response. Two nearby SNPs (CLIC rs400547; PSORS1C1 rs1265100) also regulate stress response. In mice, lung cancer susceptibility is modified by G7c which corresponds to C6orf27 of which two functional SNPs are in LD with rs3117582. We aimed to examine the relationships among these markers and and their role in lung cancer development to identify the likely causal SNP. An HLA-homozygous reference cell line panel (n=103) was used to map SNP alleles to HLA haplotypes. The BioServe Lung Cancer SNPlates (157 cases; 114 controls), in which the BAG6 association was confirmed, was used to examine the associations. MICB rs3130922 variant allele was present on multiple haplotypes except HLA-B8DR3 that harbors the risk allele of the BAG6 SNP. These two SNPs were in negative LD. rs3130922 showed a protective association (OR per allele=0.67, 95% CI=0.47 to 0.97; P=0.03) in lung cancer. In multivariable analysis, previously reported BAG6 association and MICB association both remained statistically significant. The stress response-related SNPs, and C6orf27 SNPs did not show an association. Screening of existing transcriptomics data showed that BAG6 rs3117582 correlates with expression of VARS2, which is adjacent to C6orf27. MICB rs3130922 was identified as an independent protective marker for lung cancer risk. BAG6 association may be due to mechanisms other than its effect on stress response. The complexities of the HLA complex makes a large sample size and accompanying functional studies necessary to identify the causal variant for these statistical associations.